Figure 4.

Ang1 and Ang2 function and regulation. Ang1 and Ang2 control competitive regulatory events in the vascular endothelium. Competitive binding to their common receptor, Tie2, regulates endothelial cell stability and function to inhibit or promote neoangiogenesis, respectively. Ang1 increases endothelial cell survival, tightens intercellular junctions, and increases tyrosine phosphorylation of membrane-bound Tie2. Ang2 decreases endothelial cell stability, increases vascular sprouting and leakage, and decreases tyrosine phosphorylation of Tie2, promoting angiogenesis. The resulting competitive signals combine to stabilize formed vessels, allowing them to mature, and simultaneously maintain neovascularization as dictated by tissue oxygen needs. The amounts of free Ang1 and Ang2 available for binding Tie2 are modulated by soluble Tie2 (sTie2), which is formed by proteolytic cleavage and release of the extracellular component of the membrane bound Tie 2 receptor. Circulating sTie2 binds both Ang1 and Ang2, making them unavailable for binding Tie2 to influence endothelial cell functions. Because sTie2 has a higher affinity for Ang1 than Ang 2 the amount of sTie2 exerts differential control of Ang1 and Ang2 effects. Increased levels of sTie2 favor an overall increase in new vessel sprouting because more Ang1 than Ang2 is bound up. Abbreviations are as documented in text.